Is ACOT12 p.Arg277Pro (c.830G>C) pathogenic?

ACOT12 p.Arg277Pro (c.830G>C) is classified Uncertain significance in ACOT12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: ambiguous (0.346); Very rare (popmax 0.00267%, afr).

How common is ACOT12 p.Arg277Pro (c.830G>C) in the general population?

ACOT12 p.Arg277Pro (c.830G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ACOT12 p.Arg277Pro (c.830G>C)?

AlphaMissense predicts ambiguous (score 0.346) — an in-silico prediction, not a clinical call.

ACOT12 p.Arg277Pro

c.830G>C · rs777679257 · VCV2526603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.346	ambiguous
REVEL	0.038	moderately benign-leaning
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -4.4
Regional constraint	o/e 1.04	unconstrained · MANE · 64 kb · p 0.33 · regional, not allelic
Overall
CADD	0.046	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,916 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,614,052 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ACOT12
Protein: p.Arg277Pro
Coding: c.830G>C
MANE Select: NM_130767
dbSNP: rs777679257
Type: single nucleotide variant
Location: chr5:81344985 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.21 · 3 PDB
Residue 277: the hotdog acot-type 2 domain

Full ACOT12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT12 p.Arg277Gln Likely benign ★ same residue
ACOT12 c.1518+1G>A Uncertain significance ★ same type
ACOT12 p.Ala107Val Uncertain significance ★ ⚠ same type
ACOT12 p.Ala113Pro Uncertain significance ★ ⚠ same type
ACOT12 p.Ala213Asp Uncertain significance ★ ⚠ same type
ACOT12 p.Ala274Gly Uncertain significance ★ ⚠ same type
ACOT12 p.Ala290Thr Uncertain significance ★ ⚠ same type
ACOT12 p.Ala358Ser Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/acot12-p-arg277pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown